Brexpiprazole, discovered by Otsuka, is a dopamine D2 receptor partial agonist. It has been recently approved by the FDA for the treatment of schizophrenia and as an adjunctive therapy for the treatment of major depression.
The chemical name of Brexpiprazole is (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one), and is represented by the following formula:

The synthesis of this compound was first disclosed in EP 1869025 by a process comprising palladium-catalyzed cross-coupling of non-commercial 4-bromo-benzo[b]thiophene and piperazine, followed by substitution of the piperazine with the butoxy-quinolinone derivative (Reference Example 30 and Example 1).

In addition to being expensive, the Pd-catalyzed cross-coupling reaction is not clean and gives rise to a product with reduced purity, as acknowledged by the applicant in the subsequent patent application WO 2013/015456.
WO 2013/015456 discloses a similar method for preparing Brexpiprazole, but starting from 4-chloro-benzo[b]thiophene and using smaller amounts of Pd and phosphines to cheapen the process (Examples 1-4). However, obtaining 4-chloro-benzo[b]thiophene requires a complex synthesis including a decarboxylation step that is performed under very high temperatures (145-195° C.). These reaction conditions are difficult to conduct at an industrial scale and, in our experience, this method does not proceed cleanly.

Other approaches for the synthesis of 4-piperazino-benzo[b]thiophene derivatives are disclosed in U.S. Pat. No. 5,436,246 and WO 2015/054976, where the use of organometallic compounds is avoided by introducing the piperazine derivative in a dihalobenzaldehyde at the beginning of the synthesis and then performing a cyclization reaction to obtain the benzo[b]thiophene ring. However, a final decarboxylation reaction is also needed to obtain Brexpiprazole.

In summary, the processes disclosed for the synthesis of 4-piperazino-benzo[b]thiophene derivatives require the use of organometallic reagents and/or a decarboxylation step at very high temperatures, which is an industrial limitation and does not favour clean and efficient processes.
As a consequence, it is still necessary to develop a process for the preparation of Brexpiprazole and related compounds that overcomes all or part of the problems associated with the known processes belonging to the state of the art.